The main objective of this research is to establish a definitive relationship between the structure and function of the cellular genetic apparatus (DNA integrity and regulation, RNA transcription and chromatin protein patterns) and the in vitro neoplastic transformation process. The project consists of four research programs and four experimental systems of cell culture. The programs are: (1) The cellular effects of an insult specific for DNA induced by 5-bromo-deoxyuridine substitution and uv irradiation. (2) Cellular and biochemical studies of the function and structure of the genetic apparatus as related to neoplastic transformation. (3) The effect of double-stranded polynucleotide duplexes (as interferon inducer), single-stranded polynucleotides (as reverse transcriptase inhibitors), and interferon on in vitro neoplastic transformation induced by chemical carcinogens, viruses, and treatment with BUdR plus uv irradiation. (4) Cellular transformation and infection induced by exposure to and uptake of exogenous DNA (including viral DNA) in culture. The four experimental systems are: (1) Syrian hamster embryonic fibroblasts, which will serve as the main system for in vitro morphological (neoplastic) transformation. This will be studied in conjunction with the mouse embryonic fibroblast system and the human neonatal fibroblast system. (2) Epithelial cells of liver (hepatocytes) and kidney origin, derived mainly from the rat. This sytem provides an established animal model of chemical carcinogenesis (hepatoma induced by diethylnitrosamine) and the main source of material for biochemical studies on chromatin. (3) Lymphocytes and splenic cells of hamster, mouse, rat and human origin (normal and those with infectious mononucleosis). (4) Experimental systems for Herpes simplex virus infection and transformation. These include tissues and cells of human origin (Hep-2, cervical tissues, lung cells, etc.) as well as those derived from mouse, hamster, and dog. These four vertical research programs are interwoven with the four horizontal experimental systems in cell culture.